ABSTRACT Non-atopic or Th2-low asthma is now recognized as a major subgroup of pediatric asthma. Obesity-related asthma, the most commonly reported form of pediatric non-atopic asthma, is associated with high disease burden, worse lung function, and lack of response/resistance to medications. Thus, there is an urgent need to investigate the immunobiology of non-atopic asthma to identify novel therapeutic targets. We and others have previously reported non-atopic immune responses in peripheral blood from obese asthmatic children, with elevated TH1/ TH2 ratio and increased TNF, IL-6, IFN?, and IP-10 that correlated with pulmonary function deficits in obesity-related asthma. Using RNA-Seq, we probed the biology of non-atopic responses in un- stimulated obese asthmatic CD4+ (TH) cells and found upregulation of several genes (DOCK5, VAV2, CDC42EP4, PAK3, MLK3 and PLD1) in the Cell Division Cycle 42 (CDC42) pathway. Higher CDC42EP4 and DOCK5 gene expression correlated with worse airway obstruction in obese asthmatic children. Phosphorylated p38, downstream of MLK3, and linked with steroid resistance in asthma, was higher in stimulated obese asthmatic TH cells. Small interfering RNA (siRNA)-mediated CDC42 silencing in TH cells led to lower IFN? and TNF, but not IL-4, gene expression. Together, these results suggest a novel role for the CDC42 pathway in non-atopic inflammation in obesity-related asthma. Based on these observations, we hypothesize that in obese asthmatics, upregulation of the CDC42 pathway in a non-TH2 TH cell, which is enriched in the airway, and activation of CDC42-regulated signaling pathways, contribute to steroid resistance and disease burden. To test our hypothesis, we will identify the non-TH2 TH cell with CDC42 pathway upregulation and quantify activation of CDC42-regulated signaling pathways in obese asthmatics. We will investigate enrichment of the non-TH2 TH cell in peripheral blood in 50 non-atopic obese asthmatics as compared to 50 non-atopic normal-weight asthmatics, 50 obese non-asthmatics, and 50 healthy controls. Enrichment of the non-TH2 TH cell in the airway will be investigated in a subset of 20 obese asthmatics and compared to 20 normal-weight asthmatics. Absent or attenuated cytokine suppression in the non-TH2 TH cell in response to dexamethasone will provide evidence that the cell is steroid resistant and gain of steroid sensitivity following CDC42 and/or CDC42-regulated signaling pathway inhibition will support a role of CDC42 in steroid resistance in non-atopic asthma. To identify the contribution of obesity, and of factors other than obesity, we will compare the findings in non-atopic obese asthmatics to obese non-asthmatics. Lastly, to link CDC42 activation with disease burden, we will identify a biochemical signature predictive of CDC42 activation, and investigate its contribution to disease burden in pediatric non-atopic obesity-related asthma. These studies will confirm a role of CDC42 pathway in the immunobiology and disease burden of non-atopic asthma, and will identify the non- TH2 TH cell and/or proteins in the signaling pathways as novel therapeutic targets for obesity-related asthma.